Molecular heterogeneity of the cerebriform connective tissue nevus in mosaic overgrowth syndromes

Abstract

The clinical diagnostic criteria for Proteus syndrome were defined before the discovery of the AKT1 c.49G>A; p.(Glu17Lys) causal variant and used a combination of general and specific phenotypic attributes that could be combined to make a clinical diagnosis. The most heavily weighted specific criterion was the cerebriform connective tissue nevus (CCTN). Here, we describe two individuals with connective tissue nevi (CTNs) and some general attributes of Proteus syndrome who were found to have mosaic PIK3CA variants. CTNs on the soles of individuals with PIK3CA-related overgrowth typically exhibit thickening of the soft tissues with at most a wrinkled surface, but these two patients had firm plaques with ridges and furrows characteristic of CCTNs, which was histologically confirmed in one. These data show that CCTNs are not specific to Proteus syndrome and that clinicians should be cautious in diagnosing individuals with Proteus syndrome based on the CCTN alone. Rather, a complete evaluation should include careful assessment of other attributes of the diagnostic criteria and, whenever possible, genetic analysis of affected tissue.

Phenotype and Surgical Treatment in a Case of Proteus Syndrome With Craniofacial and Oral Findings

“…Until recently, the "gyrated (skin) surfaces" (35) or "gyriform masses" (36) were so characteristic for Proteus syndrome that evidence of CCTN -in conjunction with the general category -was conclusive for clinical diagnosis of Proteus syndrome (8,37). Current studies show this specificity of the finding is not valid (38). However, the recently announced limited diagnostic specificity does not affect the importance of the finding for orienting clinical examinations in the event of a suspected Proteus syndrome (39).…”

Late‐onset Proteus syndrome with cerebriform connective tissue nevus and subsequent development of intraductal papilloma

“…Isolated CCTN with onset in the second decade of life has been previously reported but with limited evaluation for additional features of PS (Çiloğlu et al, 2015; Luo et al, 2007). While one of these individuals is reported to additionally have bone overgrowth raising suspicion of a diagnosis of PS, neither report included a genetic evaluation, making it difficult to determine if these presentations are due to AKT1 ‐mediated overgrowth, PIK3CA ‐related overgrowth, which has also been reported in CCTN, or another mechanism (Keppler‐Noreuil et al, 2019). The finding of bony overgrowth in the foot contralateral to the CCTN supports the utility of a comprehensive evaluation with x‐ray and molecular analyses of the PI3K/AKT pathway in individuals who present with apparent isolated CCTN.…”